Imidazolylacetic acid amides

ABSTRACT

Imidazolylacetic acid amides of the formula: ##SPC1## 
     Or pharmaceutically acceptable nontoxic salts thereof wherein 
     Either 
     R 1  is phenyl or cycloalkyl, unsubstituted or substituted by one or more substituents; and 
     R 2  is hydrogen; 
     Or 
     R 1  and R 2 , together with the nitrogen atom to which they are attached, form a saturated 5 to 7-membered heterocyclic ring which ring may contain an --SO 2  -- or --NY-- moiety wherein Y is alkoxycarbonyl, dialkylaminocarbonyl, or phenyl or diphenylmethyl, unsubstituted or substituted by one or more substituents and wherein said 5 to 7-membered heterocyclic ring itself is otherwise unsubstituted or substituted by one or more substituents; and 
     X 1 , x 2 , x 3  and X 4  are the same or different and are each hydrogen or halogen, 
     Are produced by 
     A. reacting a halodiphenylacetic acid amide of the formula: ##SPC2## 
     Wherein 
     R 1 , r 2 , x 1 , x 2 , x 3  and X 4  are as above defined, and 
     Hal is halogen, 
     With imidazole; or 
     B. reacting a halodiphenylacetic acid halide of the formula: ##SPC3## 
     Wherein 
     X 1 , x 2 , x 3  and X 4  are as above defined and 
     Hal is halogen 
     With imidazole to produce an imidazolide of the formula: ##SPC4## 
     Wherein 
     X 1 , x 2 , x 3  and X 4  are as above defined which in turn is transaminated by reaction with an amine of the formula: 
     
         NHR.sup.1 R.sup.2 
    
     wherein R 1  and R 2  are as above defined.

The present invention relates to imidazolyl-carboxylic acid amides,their production, antimycotic compositions embodying said compounds ofthe active ingredient, and to their use as antimycotic agents.

More particularly, the present invention is concerned withimidazolylacetic acid amides of the formula: ##SPC5##

And pharmaceutically acceptable nontoxic salts thereof wherein

Either

R¹ is phenyl or cycloalkyl, unsubstituted or substituted by one or moresubstituents; and

R² is hydrogen;

Or

R¹ and R², together with the nitrogen atom to which they are attached,form a saturated 5 to 7-membered heterocyclic ring which ring maycontain an --SO₂ -- or --NY-- moiety wherein Y is alkoxycarbonyl,dialkylamino-carbonyl, or phenyl or diphenylmethyl, unsubstituted orsubstituted by one or more substituents and wherein said 5 to 7-memberedheterocyclic ring is itself either or otherwise unsubstituted orsubstituted by one or more substituents; and

X¹, x², x³ and X⁴ are the same or different and are each hydrogen orhalogen.

The imidazolylacetic acid amides of formula (I) are produced by:

A. REACTING A HALODIPHENYLACETIC ACID AMIDE OF THE FORMULA: ##SPC6##

Wherein

R¹, r², x¹, x², x³ and X⁴ are as above defined, and

Hal is halogen,

With imidazole; or

B. REACTING A HALODIPHENYLACETIC ACID HALIDE OF THE FORMULA: ##SPC7##

Wherein

X¹, x², x³ and X⁴ are as above defined, and

Hal is halogen

with imidazole to produce an imidazolide of the formula: ##SPC8##

wherein

X¹, x², x³ and X⁴ are as above defined which in turn is transaminated byreaction with an amine of the general formula:

    NHR.sup.1 R.sup.2                                          (V)

wherein

R¹ and R² are as above defined.

The above two processes are hereinafter referred to as Process Variants(a) and (b).

When R¹ is cycloalkyl, it is preferably a cycloalkyl moiety of 5 to 7carbon atoms and especially 6 carbon atoms. Cyclopentyl, cyclohexyl andcycloheptyl are examples.

When the phenyl or cycloalkyl moieties of R¹ are substituted, they arepreferably substituted by 1 to 3 of the same or different substituents,but especially one substituent. Preferred substituents are alkyl of 1 to4 carbon atoms, especially alkyl of 1 to 3 carbon atoms, i.e., methyl,ethyl, n- and i-propyl, halogen (preferably chlorine, fluorine andbromine, especially chlorine), haloalkyl of 1 or 2 carbon atoms and 2 to5 halogen atoms (preferably chlorine or fluorine and especiallyfluorine, the trifluoromethyl moiety being preferred), and nitro.

When R¹ and R², together with the amide nitrogen atom to which they areattached, form a 5 to 7-membered heterocyclic ring, said ring maycontain a --SO₂ -- or --NY-- moiety. The preferred heterocyclic ringsare those containing 5 or 6 ring members and especially 6 ring members.When --SO₂ -- or --NY-- is contained in the 6-membered heterocyclicring, it is preferably in the p-position to the amide nitrogen. When thering contains a --NY-- moiety in the ring and Y is alkoxycarbonyl, it ispreferred that the alkoxycarbonyl be of 2 to 4 carbon atoms andespecially 2 or 3 carbon atoms, i.e., methoxycarbonyl, ethoxycarbonyland n- and i-propoxycarbonyl. When Y is a dialkylaminocarbonyl, eachalkyl moiety may be the same or different and be of 1 to 4 carbon atomsand especially 1 or 2 carbon atoms such as dimethyl, diethyl,methylethyl, methyl-n-propyl or ethylisobutyl. The phenyl anddiphenylmethyl moieties of Y are either unsubstituted or substituted bypreferably 1 to 3 of the same or different substituents selected fromthe group consisting of alkyl of 1 to 4 carbon atoms, especially alkylof 1 to 3 carbon atoms, i.e. methyl, ethyl, n- and i-propyl, halogen,preferably chlorine, fluorine or bromine and especially chlorine,halo-alkyl of 1 or 2 carbon atoms and 2 to 5 halogen atoms, preferablychlorine and fluorine and especially fluorine, for exampletrifluoromethyl, and nitro. When said 5 to 7 membered heterocyclic ringis substituted, it is substituted by one or more of the same ordifferent substituents, and preferably one substituent selected from thegroup consisting of alkyl of 1 to 4 carbon atoms, i.e., methyl, ethyl,n- and i-propyl, and n-, i- and t-butyl, especially alkyl of 1 to 2carbon atoms, or phenyl unsubstituted or substituted by a memberselected from the group consisting of alkyl of 1 to 4 carbon atoms,especially alkyl of 1 to 3 carbon atoms, i.e., methyl, ethyl, n- andi-propyl, halogen preferably chlorine, fluorine or bromine, especiallychlorine, haloalkyl of 1 or 2 carbon atoms and 2 to 5 halogen atoms,preferably chlorine and fluorine, and especially fluorine, for example,trifluoromethyl and nitro.

X¹, X², X³ and X⁴ are the same or different hydrogen or halogen, forexample, fluorine, chlorine, bromine or iodine and preferably fluorine,chlorine and bromine, especially chlorine.

Hal in formulas II and III is preferably chlorine or bromine, andespecially chlorine.

According to one embodiment of the present invention,

either

R¹ is phenyl or cycloalkly of 5 to 7 carbon atoms, unsubstituted orsubstituted by 1 to 3 substituents selected from the group consisting ofalkyl of 1 to 4 carbon atoms, halogen, haloalkyl of 1 or 2 carbon atomsand 2 to 5 halogen atoms and nitro, and

R² is hydrogen,

or

R¹ and R², together with the nitrogen atom to which they are attached,form a saturated 5 to 7-membered heterocyclic ring containing a --SO₂ --or -NY- moiety wherein Y is alkoxycarbonyl of 2 to 4 carbon atoms,dialkylaminocarbonyl of 1 to 4 carbon atoms in each alkyl moiety, phenylor diphenylmethyl, unsubstituted or substituted by 1 to 3 substituentsselected from the group consisting of alkyl of 1 to 4 carbon atoms,halogen, haloalkyl of 1 or 2 carbon atoms and 2 to 5 halogen atoms, andnitro, said heterocyclic ring being otherwise unsubstituted orsubstituted by alkyl of 1 to 4 carbon atoms or phenyl unsubstituted orsubstituted by 1 to 3 substituents selected from the group consisting ofalkyl of 1 to 4 carbon atoms, halogen, haloalkyl of 1 or 2 carbon atomsand 2 to 5 halogen atoms, and nitro, and

X¹, x², x³ and X⁴ are the same or different and are each hydrogen orhalogen.

According to another embodiment of the present invention,

either

R¹ is phenyl or cyclohexyl, unsubstituted or substituted by 1 or 2substituents selected from the group consisting of alkyl of 1 to 3carbon atoms, chlorine, fluorine, bromine, trifluoromethyl and nitro,and

R² is hydrogen,

or

R¹ and R², together with the nitrogen atom to which they are attached,form a 6-membered heterocyclic ring containing a --SO₂ -- or --NY--moiety wherein Y is phenyl, diphenylmethyl, methoxycarbonyl,ethoxycarbonyl, dimethylaminocarbonyl or diethylaminocarbonyl, saidheterocyclic ring containing a --SO₂ -- moiety being eitherunsubstituted or substituted by methyl, ethyl or phenyl, and

either

X¹, x², x³ and X⁴ are each hydrogen,

or

X¹ and X³ are each halogen and

X² and X⁴ are each hydrogen.

According to another embodiment of the present invention,

either

R¹ is cyclohexyl, or phenyl which phenyl is either unsubstituted orsubstituted by 1 or 2 substituents selected from the group consisting ofalkyl of 1 to 3 carbon atoms, chlorine, fluorine, bromine andtrifluoromethyl, and

R² is hydrogen,

or

R¹ and R², together with the nitrogen atom to which they are attached,form a 6-membered heterocyclic ring containing a --SO₂ -- or --NY--moiety wherein Y is phenyl, diphenylmethyl, methoxycarbonyl,ethoxycarbonyl, dimethylaminocarbonyl or diethylaminocarbonyl, saidheterocyclic ring containing a --SO₂ -- moiety being eitherunsubstituted or substituted by methyl, ethyl or phenyl, and

X¹, x², x³ and X⁴ are each hydrogen,

or

X¹ and X³ are chlorine and

X² and X⁴ are hydrogen.

According to another embodiment of the present invention,

either

R¹ is cyclohexyl or phenyl, unsubstituted or substituted by 1 or 2substituents selected from the group consisting of chlorine, methyl andtrifluoromethyl; and

R² is hydrogen;

or

R¹ and R², together with the nitrogen atom to which they are attached,form a 6-membered heterocyclic ring selected from the group consistingof ##SPC9##

either

X¹, x², x³ and X⁴ are each hydrogen,

or

X¹ and X³ are chlorine and

X² and X⁴ are hydrogen.

According to a further embodiment of the present invention,

either

R¹ is cyclohexyl, chlorophenyl, tolyl, trifluoromethyl phenyl,dichlorophenyl or chloromethylphenyl, and

R² is hydrogen,

or

R¹ and R², together with the nitrogen atom to which they are attached,form a 6-membered heterocyclic ring of the formula: ##SPC10##

unsubstituted or substituted by methyl, ethyl or phenyl, or ##SPC11##

wherein

Y is COOC₂ H₅, chlorophenyl, CO-N(C₂ H₅)₂ or diphenylmethyl, and

X¹, x², x³ and X⁴ are each hydrogen,

or

X¹ and X³ are chlorine and

X² and X⁴ are hydrogen.

If for example [ω-(4,4'-dichlorodiphenyl)-ω-chloromethylcarbonyl-(4)]-1,4-thiazine dioxide and imidazole are used as the starting compounds,the course of the reaction can be represented by the following equation(Process Variant (a)): ##SPC12##

If for example diphenylchloroacetic acid chloride, imidazole ando-methylaniline are used as starting compounds, the course of thereaction can be represented by the following equation (Process Variant(b)): ##SPC13##

The halodiphenylacetic acid amides used as starting compounds of theformula II are not per se known but can be produced according toprocedures per se known, for example, by reacting halodiphenylaceticacid halides of the formula III (some of which are known and can beproduced by known methods) with amides of the formula V according toprocedures described in Ber. 41, page 3593 (1908). Representativehalodiphenylacetic acid amides of formula II include:

ω,ω-diphenyl-ω-chloro-acetic acid p-chloroanilide;

ω,ω-diphenyl-ω-chloro-acetic acid m-trifluoromethylanilide;

ω,ω-diphenyl-ω-chloro-acetic acid 2-methyl-4-chloroanilide;

ω,ω-diphenyl-ω-chloro-acetic acid 2,4-dichloro-anilide;

ω,ω-diphenyl-ω-chloro-acetic acid cyclohexylamide;

ω,ω-di-(4-chlorophenyl)-ω-chloroacetic acid 2-methylanilide;

ω,ω-di-(4-chlorphenyl)-ω-chloro-acetic acid 2,5-dichloroanilide;

[ω,ω-diphenyl-ω-chloro-methylcarbonyl-(4]-1,4-thiazine dioxide;

3-methyl-4-[ω,ω-di-(4-chlorophenyl)-ω-chloro-methylcarbonyl]-1,4-thiazinedioxide;

3-ethyl-4-[ω,ω-di-(4-chlorophenyl)-ω-chloro-methylcarbonyl]-1,4-thiazinedioxide;

[ω-phenyl-ω-4-chlorophenyl-ω-chloro-methylcarbonyl-(4)-3-phenyl]-1,4-thiazinedioxide;

1-o- chlorophenyl-4-[ω,ω-diphenyl-ω-chloro-methylcarbonyl]-piperazine;

1-diethylaminocarbonyl-4-[ω,ω-diphenyl-ω-chloro-methylcarbonyl]-piperazineand

1-diphenylmethyl-4-[ω,ω-di-(4-chloro-phenyl)-ω-chloromethylcarbonyl]-piperazine.

Representative halodiphenylacetic acid halides of the formula IIIinclude:

ω,ω-diphenyl-ω-chloro-acetic acid chloride;

ω,ω-di(4-chlorophenyl)-ω-chloro-acetic acid chloride;

ω-phenyl-ω-(2-chlorophenyl)-ω-chloro-acetic acid chloride;

ω-phenyl-ω-(3-chlorophenyl)-ω-chloro-acetic acid chloride; and

ω-phenyl-ω-(4-chlorophenyl)-ω-chloro-acetic acid chloride.

Representative amines of the formula V include:

aniline;

o-methylaniline;

o- and p-dichloroaniline;

p-chloroaniline;

m-trifluoroaniline;

p-methylaniline;

p-chloro-m-methylaniline;

p-fluoroaniline;

p-bromoaniline;

o-ethylaniline;

p-nitroaniline;

o-nitroaniline;

p-nitro-o-methylaniline;

cyclohexylamine;

cyclopentylamine and

cycloheptylamine.

The pharmaceutically acceptable nontoxic salts of the compound of thepresent invention include salts formed by the reaction between theimidazolylacetic acid amide as the free base and hydrohalic acids, suchas hydrochloric and hydrobromic acids, especially hydrochloric acid,phosphoric acid, nitric acid, monofunctional and bifunctional carboxylicacids and hydroxycarboxylic acids, for example, acetic acid, maleicacid, succinic acid, fumaric acid, tartaric acid, citric acid,salicyclic acid, sorbic acid and lactic acid, and1,5-naphthalenedisulphonic acid. Hydrochloric acid is especiallypreferred.

The preferred salts are therefore the hydrohalides, for example, thehydrochloride and hydrobromide, especially the hydrochloride, thephosphate, nitrate, monofunctional and bifunctional carboxylates andhydroxycarboxylates, for example, the acetate, maleate, succinate,fumarate, tartrate, citrate, salicylate, sorbate and lactate, and1,5-naphthalene-disulphonate. The hydrochloride is especially preferred.

The reaction of the halodiphenylacetic acid and imidazole in ProcessVariant (a) can be carried out in a diluent which is inert towards thereactants and products. Such diluents include all inert polar organicsolvents. Preferred diluents are chlorinated hydrocarbons (especiallyaromatic chlorinated hydrocarbons, such as chlorobenzene); ketones(especially alower alkyl ketones, such as acetone and diethyl ketone);nitriles (especially those having up to 6 carbon atoms, such asacetonitrile); amides (especially lower dialkylformamides, such asdimethylformamide); and sulphoxides (especially lowerdialkylsulphoxides, such as dimethylsulphoxide).

As acid-binding agents, it is possible to use, in Process Variant (a),all the usual acid-binding agents. These include organic and inorganicbases (preferably alkali metal hydroxides, such as sodium hydroxide andpotassium hydroxide) and tertiary organic bases (such as trialkylamines,for example triethylamine). In Process Variant (a) according to theinvention, we prefer particularly to use an excess of imidazole insteadof a separate acid-binding agent.

In the Process Variant (a), the reaction temperatures can be varied overa substantial range. In general, the reaction is carried out at between50°C and 150°C, preferably between 80°C and 120°C.

The reaction in Process Variant (a) can be carried out under normalpressure but also under elevated pressure. The reaction is preferablycarried out under normal pressure.

In carrying out the process according to the invention Process Variant(a), 1 to 5 (preferably 1 to 2) mols of imidazole and additionally 1 to5 (preferably 1 to 2) equivalents of the acid-binding agent (for exampleimidazole or triethylamine) are generally employed per 1 mol of theimidazolylcarboxylic acid amides of formula II.

As an example, for the isolation of the free amides of the formula Iaccording to the present invention carried out according to knownmethods, the solvent is distilled from the reaction mixture, the residueis digested with ice water and the undissolved solid is filtered off andpurified by recrystallization. Thereafter any desired salts can beproduced by generally customary methods, for example by dissolving thefree amide of the formula I in an organic solvent and adding therequisite amount of acid.

The solvents already mentioned in connection with Process Variant (a)can also be used as diluents in the reaction, according to theinvention, of the halodiphenylacetic acid halides of the formula IIIwith imidazole in Process Variant (b).

The acid-binding agent used in the first reaction step in ProcessVariant (b) (reaction of halodiphenylacetic acid halides of the generalformula III with imidazole) is preferably an excess of imidazole,appropriately about 4 to 10, preferably 4 to 5, mols of imidazole per 1mol of starting compound of the formula III.

In the reaction of the compounds of the formula III with imidazole(Process Variant (b)), the reaction temperatures can be varied within asubstantial range. In general, the reaction is carried out at between50°C and 100°C, preferably between 50°C and 100°C.

The imidazolides of the formula IV which are produced in the firstreaction step are preferably reacted further without intermediateisolation. However, a prior isolation is possible within the scope ofthe invention.

In the second reaction step of Process Variant (b) (reaction of theimidazolide of the formula IV with the amine of the formula V) thereaction temperatures can be varied within a substantial range. Ingeneral, the reaction is carried out between 50°C and 150°C, preferablybetween 80°C and 150°C.

In carrying out the second reaction step in Process Variant (b), 1 to 5,more perferably 1 to 2, mols of amine of the formula V are preferablyused per 1 mole of imidazolide of the formula IV. Using higher or lowerthan stoichiometric ratios does not adversely influence the outcome ofthe reaction.

The working up and isolation of the imidazolyl-carboxylic acid amides ofthe formula I can be carried out according to customary methods, forexample as described in connection with Process Variant (a). Thereafter,the salts can be produced according to customary methods, for example asdescribed above.

The following compounds are representative of the imidazolylacetic acidamides of the present invention:

4-[ω,ω-di-(chlorophenyl)-ω-imidazolyl-(1)-methylcarbonyl]-1,4-thiazinedioxide;

ω,ω-diphenyl-ω-imidazolyl-(1)-acetic acid 3-trifluoromethylanilide;

ω,ω-diphenyl-ω-imidazolyl-(1)-acetic acid 2-methyl-4-chloro-anilide;

ω,ω-diphenyl-ω-imidazolyl-(1)-acetic acid 2,4-dichloroanilide;

ω,ω-diphenyl-ω-imidazolyl-(1)-acetic acid cyclohexylamide;

4-[ω,ω-di-(4-chlorophenyl)-ω-imidazolyl-(1)-methylcarbonyl]-3-phenyl-1,4-thiazinedioxide;

4-[ω,ω-diphenyl-ω-imidazolyl-(1)-methylcarbonyl]-1-ethoxycarbonyl-piperazineand

4-[ω,ω-diphenyl-ω-imidazolyl-(1)-methylcarbonyl]-1-o-chlorophenyl-piperazine.

The imidazolylacetic acid amides and the salts of the present inventionexhibit strong antimycotic activity. They exhibit a broad spectrum ofantimycotic activity especially against dermatophytes and blastomycetes,as well as biphase fungi, for example against species of Candida such asCandida albicans, species of Epidermophyton such as Epidermophytonfloccosum, species of Aspergillus such as Aspergillus niger, species ofTrichophyton such as Trichophyton mentagrophytes, species of Microsporonsuch as Microsporon felineum, and species of Penicillium such asPenicillium commune.

The compounds of the present invention are deemed to be useful in thetreatment of dermatomycoses and systemic mycoses in humans caused byTrichophyton mentagrophytes and other species of Trichophyton, speciesof Microsporon, Epidermophyton floccosum, blastomycetes and biphasefungi as well as moulds.

The compounds of the present invention are useful in veterinary medicineand the treatment of dermatomycoses and systemic mycoses, especiallythose caused by the above mentioned pathogens.

The present invention also includes pharmaceutical compositionscomprising an imidazolylacetic acid amide of the present invention incombination with a pharmaceutically acceptable nontoxic, inert diluentor carrier.

The pharmaceutical compositions of the present invention contain a majoror minor amount e.g. 99.5% to 0.1%, preferably 95% to 0.5% of at leastone imidazolylacetic acid amide as above defined in combination with apharmaceutically acceptable nontoxic, inert diluent or carrier, thecarrier comprising one or more solid, semi-solid or liquid diluent,filler and formulation adjuvant which is nontoxic, inert andpharmaceutically acceptable. Such pharmaceutical compositions arepreferably in dosage unit form; i.e., physically discrete unitscontaining a predetermined amount of the drug corresponding to afraction or multiple of the dose which is calculated to produce thedesired therapeutic response. The dosage units can contain one, two,three, four or more single doses or, alternatively, one half, third orfourth of a single dose. A single dose preferably contains an amountsufficient to produce the desired therapeutic effect upon administrationat one application of one or more dosage units according to apredetermined dosage regimen, usually a whole, half, third or quarter ofthe daily dosage administered once, twice, three or four times a day.Other therapeutic agents can also be present.

Although the dosage and dosage regimen must in each case be carefullyadjusted, utilizing sound professional judgment and considering the age,weight and condition of the recipient, the route of administration andthe nature and gravity of the illness, generally the dosage will be from30 to 250, and preferably 50 to 200, mg/kg of body weight per day. Insome instances a sufficient therapeutic effect can be obtained at alower dose while in others, a large dose will be required.

Oral administration can be effected utilizing solid and liquid dosageunit forms such as powders, tablets, dragees, capsules, granulates,suspensions, solutions and the like.

Powders are prepared by comminuting the compound to a suitable fine sizeand mixing with a similarly comminuted pharmaceutical carrier such as anedible carbohydrate as for example starch, lactose, sucrose, glucose ormannitol. Sweetening, flavoring, preservative, dispersing and coloringagents can also be present.

Capsules are made by preparing a powder mixture as described above andfilling formed gelatin sheaths. Glidants and lubricants such ascolloidal silica, talc, magnesium stearate, calcium stearate or solidpolyethylene glycol can be added to the powder mixture before thefilling operation. A disintegrating or solubilizing agent such asagar-agar, calcium carbonate or sodium carbonate can also be added toimprove the availability of the medicament when the capsule is ingested.

Tablets are formulated for example by preparing a powder mixture,granulating or slugging, adding a lubricant and disintegrant andpressing into tablets. A powder mixture is prepared by mixing thecompound, suitably comminuted, with a diluent or base as describedabove, and optionally with a binder such as carboxymethyl, cellulose, analginate, gelatin, or polyvinyl pyrrolidone, a solution retardant suchas paraffin, a resorption accelerator such as a quaternary salt and/oran absorption agent such as bentonite, kaolin or dicalcium phosphate.The powder mixture can be granulated by wetting with a binder such assyrup, starch paste, acacia mucilage or solutions of cellulosic orpolymeric materials and forcing through a screen. As an alternative togranulating, the powder mixture can be run through the tablet machineand the resulting imperfectly formed slugs broken into granules. Thegranules can be lubricated to prevent sticking to the tablet formingdies by means of the addition of stearic acid, a stearate salt, talc ormineral oil. The lubricated mixture is then compressed into tablets. Themedicaments can also be combined with free flowing inert carriers andcompressed into tablets directly without going through the granulatingor slugging steps. A clear or opaque protective coating consisting of asealing coat of shellac, a coating of sugar or polymeric material and apolish coating of wax can be provided. Dyestuffs can be added to thesecoatings to distinguish different unit dosages.

Oral fluids such as solutions, syrups and elixirs can be prepared indosage unit form so that a given quantity contains a predeterminedamount of the compound. Syrups can be prepared by dissolving thecompound in a suitably flavored aqueous sucrose solution while elixirsare prepared through the use of a nontoxic alcoholic vehicle.Suspensions can be formulated by dispersing the compound in a nontoxicvehicle. Solubilizers and emulsifiers such as ethoxylated isostearylalcohols and polyoxyethylene sorbitol esters, preservatives, flavoradditives such as peppermint oil or saccharin, and the like can also beadded.

Where appropriate, dosage unit formulations for oral administration canbe microencapsulated. The formulation can also be prepared to prolong orsustain the release as for example by coating or embedding particulatematerial in polymers, wax or the like.

Parenteral administration can be effected utilizing liquid dosage unitforms such as sterile solutions and suspensions intended forsubcutaneous, intramuscular or intravenous injection. These are preparedby suspending or dissolving a measured amount of the compound in anontoxic liquid vehicle suitable for injection such as an aqueous oroleaginous medium and sterilizing the suspension or solution.Alternatively, a measured amount of the compound is placed in a vial andthe vial and its contents are sterilized and sealed. An accompanyingvial or vehicle can be provided for mixing prior to administration.Nontoxic salts and salt solutions can be added to render the injectionisotonic. Stabilizers, preservatives and emulsifiers can also be added.

Rectal administration can be effected utilizing suppositories in whichthe compound is admixed with low melting water soluble or insolublesolids such as polyethylene glycol, cocoa butter, higher esters as forexample myristyl palmitate, or mixtures thereof.

Topical administration can be effected utilizing solid dosage unit formssuch as powders or liquid or semiliquid dosage unit forms such assolutions, suspensions, ointments, pastes, creams and gels. The powdersare formulated utilizing such carriers as talc, bentonite, silicic acid,polyamide powder and the like. Liquid and semiliquid formulations canutilize such carriers, in addition to those described above, aspolyethylene glycol, vegetable and mineral oils, alcohols such asisopropanol and the like. Other excipients such as emulsifiers,preservatives, colorants, perfumes and the like can also be present.Formulations can also be administered as an aerosol, utilizing the usualpropellants such as the chlorofluorohydrocarbons.

The preferred daily dose is 1.5 to 22.5 g, preferably 2.5 to 18.0 g, ofactive agent.

While the compounds of the present invention are suitable for oral,parenteral (for example intramuscular, intraperitoneal and intravenousadministration), rectal, or topical application, oral administration andtopical application are particularly preferred.

The preferred pharmaceutical compositions are therefore those which aresuitable for oral or topical administration, such as tablets, pills,granules, lotions and ointments.

The following in vitro and in vivo experimental data illustrate theantimycotic activity of the compounds of the present invention.

Determination of the anti-mycotic spectrum of action in vitro, by theseries dilution test Description of the experiments

The nutrient substrates used were Sabouraud's milieu d'epreuve fordermatophytes and moulds, and meat broth-glucose bouillon forblastomycetes and biphase fungi.

The incubation temperature was 28°C and the incubation time was 24 to 96hours.

The experiment results are summarized in Table A.

                                      Table A                                     __________________________________________________________________________    Minimum inhibitory concentration in γ/ml of nutrient medium             Compound from                                                                         Trichophyton                                                                              Candida      Penicillium                                                                          Aspergillus                                                                          Microsporon                    Example No.                                                                           mentagrophytes                                                                            albicans     commune                                                                              niger  felineum                               n.s.  w.s.  n.s.   w.s.         n.s.                                                                             w.s.                               __________________________________________________________________________    13      10    40    >100   --    >100   1* 100*  100                          4       64    64    >64    >64   >64    -- --    --                           2       100   --    >100   --    >100   -- --    --                           12      64.sup.+                                                                            --    64.sup.+                                                                             >64   >64    -- --    --                           7       32*   >64   4*     8     >64    -- --    --                           5       32    32    8.sup.+                                                                              64.sup.+                                                                            >64    -- --    --                           6       1*    8     1*     32*    64*   4* 8*     4*                          11      32    32    >64    >64   >64    -- --    --                           __________________________________________________________________________     Legend:                                                                       w.s. = with 30% serum added                                                   n.s. = no serum added                                                         * = 90% inhibition of growth                                                  + = 50% inhibition of growth                                             

Anti-mycotic action of the compounds according to the invention inanimal experiments

a. Action on Quinckeanum trichophytosis in white mice, on oraladministration

With doses of 2 × 100 mg/kg administered orally once daily up to theeighth day of the infection, it was possible to suppress the developmentof the Quinckeanum infection in mice. After administration of thecompounds according to the invention, 0 to 2 out of 20 treated mice, incontrast to 19 out of 20 animals of the untreated control, showedscutula, which are to be regarded as a typical sign of infection ofQuinckeanum trichophytosis, ten day after the infection.

b. Candidosis of mice

Mice of type SPF-CF₁ were intravenously infected with 1 to 2 × 10⁶Candida cells which were suspended in physiological sodium chloridesolution.

One hour before and 7 hours after infection, the animals were treatedorally with 50, 75, 100 and 150 mg of the compounds according to theinvention/kg of body weight. Untreated control animals died of theinfection, 3 to 6 days after infection.

The experimental results are summarised in Table B.

                  Table B                                                         ______________________________________                                        Action in Candidosis of mice                                                  Compound from   Action in the case of Candida                                 Example No.     albicans                                                      ______________________________________                                        2               +                                                             12              +                                                             7                ++                                                           ______________________________________                                         Legend:                                                                        + = 50% survivals on 6th day after infection                                 ++ = 60 to 80% survivials on 6th day after infection.                    

The following Examples illustrate the invention.

EXAMPLE 1 Process Variant (a) ##SPC14##

134.5 g (0.4 mol) of chlorodiphenylacetic acid o-methylanilide aredissolved in 500 ml of anhydrous acetonitrile and 40.4 g (0.4 mol) oftriethylamine are added. 27.2 g (0.4 mol) of imidazole are addeddropwise thereto at room temperature, and the reaction mixture is heatedto the boil for 16 hours. After cooling, the solvent is distilled off invacuo until one-quarter remains and the resulting residue is digestedwith ice water. The insoluble product is filtered off, dried and brieflyheated to the boil with acetone. The residue is filtered off and dried.

47.5 g (32.4% of theory) of ω,ω-diphenyl-ω-imidazolyl-(1)-acetic acido-methylamilide, of melting point 141° to 143°C, are obtained.

Process Variant (b)

52.8 g (0.2 mol) of chlorodiphenylacetic acid chloride are dissolved in300 ml of anhydrous acetonitrile and 55 g (0.8 mol) of imidazole areadded. After heating for 16 hours under reflux, the mixture is cooled,21.5 g (0.2 mol) of o-methylaniline are added and the mixture is againheated to the boil under reflux for 16 hours. Thereafter it is worked upas indicated above.

26.1 g (34.5% of theory) of ω,ω-diphenyl-ω-imidazolyl-(1) -acetic acido-methylanilide of melting point 141° to 143°C are obtained.

EXAMPLE 2 ##SPC15##

42.9 g (0.1 mol) of[ω,ω-di-(4-chlorophenyl)-ω-chloromethylcarbonyl-(4)]-1,4-thiazinedioxide are dissolved in 150 ml of anhydrous acetonitrile and 13.6 g(0.2 mol) of imidazole are added dropwise thereto, at the boil.Thereafter the mixture is heated to the boil for 16 hours and cooled,and the solvent is distilled from the reaction mixture in vacuo, exceptfor a small residual amount. The semi-crystalline residue is stirredwith ice water. The solid product thereby produced is filtered off andrecrystallized from acetonitrile.

30.6 g (66% of theory) of[ω,ω-di(4-chlorophenyl)-ω-imidazolyl-(1)-methylcarbonyl-(4)]-1,4-thiazinedioxide of melting point 159° to 163°C are obtained.

Alternatively, 0.2 mol of ω,ω-di-(4-chlorophenyl)-ω-chloroacetic acidchloride are dissolved in 300 ml of anhydrous acetonitrile and 0.8 molof imidazole are added. After heating for 16 hours under reflux, themixture is cooled, 0.2 mol of 1,4triazine-1,1-dioxide are added and themixture is again heated to the boil under reflux for 16 hours.Thereafter it is worked up as indicated above.

The compounds in Table 1 below are produced in a manner analoguos tothat described in Examples 1 and 2 from the reactants set forth inTables 2 and 3.

                                      Table 1                                     __________________________________________________________________________    Example                                                                            X.sup.1                                                                           X.sup.2                                                                          X.sup.3                                                                           X.sup.4                                                                          R.sup.1                R.sup.2                                                                          Melting                          No.                                          point                                                                         °C                        __________________________________________________________________________    3    H   H  H   H                            206-208                          4    H   H  H   H                         H  219-220                          5    H   H  H   H                         H  178-179                          6    H   H  H   H                         H  115                              7    H   H  H   H                         H  166-168                                             R.sup.1 and R.sup.2                                        8    H   H  H   H                            272-275                          9    H   H  H   H                            266-268                          10   H   H  H   H                            256-258                          11   4-Cl                                                                              H  4-Cl                                                                              H                            103-104                          12   H   H  H   H                            156-158                          13   H   H  H   H                            260-262                          14   H   H  H   H                            166-168                          15   H   H  H   H                            220-222                          __________________________________________________________________________

                  Table 2                                                         ______________________________________                                        The compounds of Examples 3 through 15 are produced                           according to Process Variant (a) by reacting imidazole with:                  Example                                                                       No.                                                                           3      w,w-diphenyl-w-chloro-acetic acid p-chloroanilide                      4      w,w-diphenyl-w-chloro-acetic acid m-trifluoroemethyl-                          anilide                                                               5      w,w-diphenyl-w-chloro-acetic acid 2-methyl-4-chloro                            anilide                                                               6      w,w-diphenyl-w-chloro-acetic acid 2,4-dichloro-                                anilide                                                               7      ----                                                                   8      [w,w-diphenyl-w-chloro-methylcarbonyl]-1,4-thiazine                            dioxide                                                               9      3-methyl-4-[w,w-diphenyl-w-chloro-methylcarbonyl]-                             1,4-thiazine dioxide                                                  10     3-ethyl-4-[w,w-diphenyl-w-chloro-methylcarbonyl]-                              1,4-thiazine dioxide                                                  11     3-phenyl-4-[w,w-di-(4-chlorophenyl)-w-chloromethyl-                            carbonyl]-1,4-thiazine dioxide                                        12     1-Ethoxycarbonyl-4-[w,w-diphenyl-w-chloromethyl-                               carbonyl]-piperazine                                                  13     1-O-chlorophenyl-4-[w,w-diphenyl-w-chloro-methyl-                              carbonyl]-piperazine                                                  14     1-diethylaminocarbonyl-4-[w,w-diphenyl-w-chloro-                               methylcarbonyl]-piperazine                                            15     1-diphenylmethyl-4-[w,w-di-(4-chloro-phenyl)-w-                                chloro-methylcarbonyl]-piperazine                                     ______________________________________                                    

                  Table 3                                                         ______________________________________                                        The compounds of Examples 3 through 15 are produced                           according to Process Variant (b) by reacting imidazole with:                  Example                                                                       No.                                                                           2      w,w-di-(p-chlorphenyl)-w-chloro-acetic acid chloride                   4      w,w-diphenyl-w-chloro-acetic acid chloride                             5      w,w-diphenyl-w-chloro-acetic acid chloride                             6      w,w-diphenyl-w-chloro-acetic acid chloride                             7      w,w-diphenyl-w-chloro-acetic acid chloride                             8      ----                                                                   9      ----                                                                   10     ----                                                                   11     w,w-di-(4-chlorophenyl)-w-chloro-acetic acid chloride                  12     w,w-diphenyl-w-chloro-acetic acid chloride                             13     w,w-diphenyl-w-chloro-acetic acid chloride                             14     ----                                                                   15     ----                                                                   to produce an imidazolide which is thereafter transaminated                   by reaction with an amine.                                                    ______________________________________                                    

what is claimed is:
 1. An imidazolylacetic acid amide of the formula:##SPC16##or a pharmaceutically acceptable nontoxic salt thereof whereinR¹ is phenyl or cyclohexyl, unsubstituted or substituted by 1 or 2substituents selected from the group consisting of alkyl of 1 to 3carbon atoms, chlorine, fluorine, bromine, trifluoromethyl and nitro,and R² is hydrogen; and X¹, x², x³ and X⁴ are the same or different andare each hydrogen or halogen.
 2. A compound according to claim 1whereineitherX¹, x², x³ and X⁴ are each hydrogen, orX¹ and X³ are eachhalogen and X² and X⁴ are each hydrogen.
 3. A compound according toclaim 2 whereinR¹ is cyclohexyl or phenyl, said phenyl beingunsubstituted or substituted by 1 or 2 substituents selected from thegroup consisting of alkyl of 1 to 3 carbon atoms, chlorine, fluorine,bromine and trifluoromethyl, and eitherX¹, x², x³ and X⁴ are eachhydrogen, orX¹ and X³ are each chlorine and X² and X⁴ are each hydrogen.4. A compound according to claim 1 whereinR¹ is cyclohexyl or phenyl,unsubstituted or substituted by 1 or 2 substituents selected from thegroup consisting of chlorine, methyl and trifluormethyl; and eitherX¹,x², x³ and X⁴ are each hydrogen, orX¹ and X³ are chlorine and X² and X⁴are hydrogen.
 5. A compound according to claim 1 whereinR¹ iscyclohexyl, chlorophenyl, tolyl, trifluoromethylphenyl dichlorophenyl orchloromethylphenyl; and eitherX¹, x², x³ and X⁴ are each hydrogen orX¹and X³ are chlorine and X² and X⁴ are hydrogen.
 6. A compound accordingto claim 1 in the form of a salt wherein said salt is selected from thegroup consisting of the hydrochloride, the hydrobromide, the phosphate,nitrate, acetate, maleate, succinate, fumarate, tartrate, citrate,salicylate, sorbate, lactate, and 1,5-naphthalene-disulphonate.
 7. Thesalt according to claim 6 which is the hydrochloride salt.
 8. Thecompound according to claim 1 which is ##SPC17##
 9. The compoundaccording to claim 1 whereinR¹ is ##SPC18## and R², X¹, X², X³ and X⁴are each hydrogen.
 10. The compound according to claim 1 whereinR¹ is##SPC19## and R² , X¹, X², X³ and X⁴ are each hydrogen.
 11. The compoundaccording to claim 1 whereinR¹ is ##SPC20## R², x¹, x², x³ and X⁴ areeach hydrogen.
 12. The compound according to claim 1 whereinR¹ is##SPC21## and R², X¹, X², X³ and X⁴ are each hydrogen.
 13. The compoundaccording to claim 1 whereinR¹ is ##SPC22## and R², X¹, X², X³ and X⁴are each hydrogen.